Genome duplication is an important speciation mechanism for all eukaryotes, especially animals and plants. On one hand, genome duplication provides additional genetic material for adaptive evolution and natural variation; on the other, genome duplication results in chromosome imbalance and intrinsic instability of polyploids and aneuploids. Moreover, increased gene and genome dosage may cause abnormal cell cycle control and disease syndromes. Thus, to take advantage of novel variation and fitness but avoid deleterious effects, polyploid cells must establish a new relationship between alien cytoplasm and nuclei and reprogram expression patterns of orthologous and paralogous genes derived from their progenitors. Some duplicate genes must be silenced, whereas others may be instantly expressed or spatially and temporally regulated. Indeed, our recent studies indicate that genetic and epigenetic regulation is involved in reprogramming genome stability and gene expression in polyploids. Here we test hypotheses concerning fundamental biological and genetic consequences of genome duplication. We will determine how genome stability is maintained in newly formed polyploids. We will test if gene activation and silencing is stable or stochastic in natural and new polyploids. Changes in chromatin and DNA methylation status of candidate genes will be monitored when the silenced genes are reactivated. The hypothesis that orthologous genes are controlled independently of chromosomal location will be tested by determining if transgenes at ectopic locations are silenced. By silencing active orthologous genes, we will determine if silencing decisions are randomly made. We will test if RNA interference is involved in silencing endogenous redundant genes as it is in silencing transgenes and developmentally regulated genes. Furthermore, we will explore the role of alien cytoplasmic and nuclear compatibility in the evolutionary success of polyploids. Elucidating the molecular basis of genome stability and gene expression in recent and established polyploids will provide fundamental knowledge needed to understand mechanisms for natural variation and epigenetic phenomena important in medicine, such as X-chromosome inactivation, gametic imprinting, and disease syndromes.